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Biologics License

Application:Recombinant Human

Activated Protein C (rhAPC)

[drotrecogin alfa (activated)]

Xigris for Severe Sepsis

Anti-Infective Advisory Committee

October 16, 2001

FDA/CBER

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Sponsors Proposed Indication

rhAPC is indicated for the

treatment of pediatric and adultpatients with sepsis associated

with acute organ dysfunction

(severe sepsis). Treatment withrhAPC reduces mortality in

patients with severe sepsis.

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Overview of Drotrecogin

Product Development 13 phase 1 studies:

8 studies healthy volunteers

(110 patients) 3 studies end-stage renal disease

(30 patients)

1 study heterozygous Protein C deficiency

(9 patients)

1 study Purpura fulminans

(42 patients)

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Overview of Drotrecogin

Product Development 1 study, phase 2, randomized, double-blind,

placebo-controlled study of 131 patients withsevere sepsis

1 study, phase 3, randomized, double-blind,placebo-controlled study of 1690 patients withsevere sepsis

Pediatric study in 83 patients with severesepsis

Ongoing, uncontrolled trials in > 500 patients

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Study Design:

Phase 2 Study Randomized, placebo-controlled,

dose-ranging, multicenter

131 patients with severe sepsis rhAPC: 12, 18, 24 or 30 ug/kg/hr

continuous iv infusion 48 or 96 hours

Outcome measures Pharmacodynamic & pharmacokinetic

Safety

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Results:

Phase 2 Study

Treatment Patients

Total (N)

28-Day Mortality

N (%)

rhAPC(all doses)

90 26 (29%)

Placebo 41 14 (34%)

Total 131 P=0.55

Chi-square test

Phase 3 dose chosen based on PD effects on D-dimers in

phase 2

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Study Design:

Phase 3 Study Randomized, double-blind, single dose,

placebo-controlled, multicenter study

rhAPC: 24 ug/kg/hr iv infusion for 96 hours

2280 patients planned for enrollment

Inclusion: Severe sepsis

3 of 4 SIRS criteria

1 organ failure

Suspected or proven infection

Exclusion: patients at high risk for bleeding

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Study Design:

Final Statistical Analysis Plan Primary efficacy endpoint: 28 day all cause

mortality

Primary efficacy analysis: Cochran-Mantel-

Haenszel test stratified by preinfusion:

APACHE II quartile

Age class

Protein C activity class 2 interim analyses:

760 patients (alpha level=0.0002), October 1999

1520 patients (alpha level=0.0118), June 2000

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Study Design:

Prospectively Defined Secondary

Analyses Mortality treatment effect by:

Protein C levels

APACHE II Age

Gender, origin

SOFA, SIRS

Organ Failure

Shock, ARDS, DIC

AT III levels

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Results:

Demographics Age, Gender, Origin

DEMOGRAPHIC PARAMETERS rhAPC (850)

(%)

Placebo (840)

(%)

AGE

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Results:Demographics Disease Severity

rhAPC (850)(%)

Placebo (840)(%)

PREEXISTING CONDITIONS

Hypertension 38 35

Myocardial infarction 12 14Congestive cardiomyopathy 6 9

Diabetes 21 22

Pancreatitis 3 4

Liver disease 2 3

COPD 22 26

Cancer 17 19

Recent Trauma 3 5

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Results:

Demographics Disease Severity

RECENT

SURGICAL

HISTORY

rhAPC (850)

(%)

Placebo (840)

(%)

Elective surgery 6 6

Emergency

Surgery

21 21

No history of

surgery

74 73

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Results:

Demographics Disease SeverityMEASURE OF DISEASE

SEVERITY

rhAPC (850) Placebo (840)

APACHE II score mean 25 25

Mechanical ventilation (%) 73 78

Shock (%) 70 72

Use of any vasopressor (%) 72 76

Use of dobutamine (%) 14 14

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Results:

Demographics Disease Severity

# of ORGAN

FAILURES (OF)

rhAPC (850)

(%)

Placebo (840)

(%)

1 25 24

2 32 33

3 25 26

4 14 14

5 4 4

*Time from 1stOF to start drug 18 hours 17 hours

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Results:

Phase 3 Study

Primary Efficacy EndpointTreatment Patients

(N)

28-Day

Mortality

N (%)

rhAPC 850 210 (24.7%)

Placebo 840 259 (30.8%)

Total 1690 Stratified, CMH

p=0.005

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Results:Primary Efficacy Endpoint

ITT Population

0 4 8 12 16 20 24 28

TIME (Days)

0

20

40

60

80

100

SURVIVAL(%)

Placebo rhAPC

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Review of Mortality Effect

by Patient Subgroups

Patient age

Disease severity

APACHE II Organ failure

Shock

Hematologic parameters Protein C DIC

Use of heparin

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Results:

Mortality as a Function of Age

Age

(years)

rhAPC

(850)

Mortality

(%)

Placebo

(840)

Mortality

(%)

Mort

Diff

(%)

RR 95%

CI

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Results:

Mortality as a Function of Age

010

20

30

4050

60

18-20

n= (16)

21-30

(86)

31-40

(136)

41-50

(217)

51-60

(286)

61-70

(356)

71-80

(451)

81-90

(129)

91-100

(13)

Age (years)

M

ortality(%)

Placebo rhAPC

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Patient age

Disease severity


Shock

Hematologic parameters Protein C

DIC

Use of heparin

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APACHE II: Disease severity

Acute physiology and chronic health

evaluation (Knaus 1985)

Index used to predict mortality in ICUsetting

Uses physiologic measurements, age

and chronic health status

R lt

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Results:Mortality as a Function of

APACHE II at Study EntryApache

Quartile

(score)

rhAPC (850)

Mortality

(%)

Placebo (840)

Mortality

(%)

Mort

Diff

(%)

RR 95% CI

1st

(3-19)33 /218

(15)26 /215

(12)+3 1.25 0.78,2.02

2nd

(20-24)

49 /218

(22)

57 /222

(26)

-4 0.88 0.63,

1.22

3rd

(25-29)48 /204

(24)58 /162

(36)-12 0.66 0.48,

0.91

4th

(30-53)

80 /210

(38)

118 /241

(49)

-11 0.78 0.63,

0.96

interaction p = 0.09

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Results:Mortality as a Function of APACHE II

0

10

20

30

40

5060

70

80

5-10

n=(24)

10-15

(152)

15-20

(330)

20-25

(456)

25-30

(345)

30-35

(227)

35-40

(102)

40-45

(37)

45-50

(13)

APACHE II

Mortality(%)

Placebo rhAPC

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Results:

Mortality as a Function of

APACHE II QuartilesAPACHE II

Quartiles

(score)

rhAPC

(850)

Mortality

(%)

Placebo

(840)

Mortality

(%)

Mort

Diff

(%)

RR 95%

CI

Q1+Q2

(

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Results:

Mortality as a Function of Organ Failure

# OF rhAPC (850)

Mortality (%)

Placebo (840)

Mortality (%)

Mort

Diff (%)

RR 95% CI

1 42 /215

(20)

43 /203

(21)

-1 0.92 0.63,

1.35

2 56 /270

(21)

71/273

(26)

-5 0.80 0.59,

1.08

3 56 /214

(26)

75 /218

(34)

-8 0.76 0.57,

1.02

4 46 /119

(39)

54 /116

(47)

-8 0.83 0.62,

1.12

5 10 /31

(32)

16 /30

(53)

-21 0.60 0.33,

1.11

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Results:Mortality as a Function Disease

Severity (Organ Failure)

0

10

20

30

40

50

60

1 2 3 4 5

Number of Organ Dysfunctions

Mortality(%

)

Placebo

rhAPC

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Shock

Shock rhAPC

Mortality

(%)

Placebo

Mortality

(%)

Mort

Diff

(%)

RR 95%

CI RR

No 53 /252

(21)

53 /238

(22)

-1 0.94 0.67,

1.32

Yes 157 /598

(26)

206 /602

(34)

-8 0.77 0.64,

0.91

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Results:

Summary of Treatment Effect by

APACHE II & Organ Failure & ShockALL PATIENTS

APACHE - Q1

APACHE - Q2

APACHE - Q3

APACHE - Q4

OF - 1

OF - 2

OF - 3

OF - 4

OF - 5

SHOCK - Absent

SHOCK - Present

0.1 1 10rhAPC Better Placebo Better

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Patient age

Disease severity


Shock


DIC

Use of heparin

R lt

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Results:


Protein C LevelsProtein C

Def

rhAPC

Mortality

(%)

Placebo

Mortality

(%)

Mort

Diff

(%)

RR 95% CI

Deficient(80%)

182 /709(26)

215 /670(32)

-6 0.80 0.68,0.95

Not

deficient

(>80%)

14 /90

(16)

28 /105

(27)

-11 0.58 0.33,

1.04

Unknown

or Absent

14 /51

(28)

16 /65

(25)

+3 1.12 0.60,

2.07

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Results:

Mortality in Patients with

Laboratory Evidence of DIC

DIC rhAPC

Mortality(%)

Placebo

Mortality(%)

Mort

Diff

(%)

RR 95%

CI

DIC 196 /800

(25)

243 /774

(31)

-6 0.78 0.67,

0.92

Unknownor Absent 14 /49

(29)16 /66(24)

+5 1.18 0.65,2.16

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Patient age

Disease severity


Shock


DIC

Use of heparin

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Results:Mortality as a Function of Heparin Use

rhAPCTotal N (%)

PlaceboTotal N (%)

Mort Diff(%)

Heparin

At

baseline

532 138 (26) 559 170 (30) 4

During

infusion

634 158 (25) 637 179 (28) 3

Not on Heparin

At

baseline

318 72 (23) 281 89 (32) 9

During

infusion

216 52 (24) 203 80 (39) 15

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Morbidity Outcomes

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Results:

Functional Status at Day 28

32.3 30.6

7.2 7.9

23.5 20.9

12.29.8

24.730.8

rhAPC PLACEBO0%

20%

40%

60%

80%

100%

Home

NursHome

Hosp

ICU

DIED

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Protocol Amendment June 1999-after trial initiated

Sponsor blinded Before 1stinterim analysis

Primary Analytic Plan Elimination of PC deficiency status and septic

shock as covariates from the CMH analysis Inclusion and Exclusion Criteria

Esophageal varices

Cirrhosis

Transplant patients Moribund patients

Pancreatitis

Malignancy

Definition of OF

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Effect of Protocol Change:Original vs. Amended Protocol

malignancy (21% vs 16%)

immunosuppressed (11% vs. 8%)

withdrawal of life support (17% vs. 13%)

APACHE II chronic health points (25% vs. 17%)

non-sepsis related death (5% vs. 4%)

at nursing home facilities (8% vs. 6%)

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Effect of Protocol Change:Original vs. Amended Protocol

Higher Il-6 median levels in amended

(566 ug/ml vs. 389 ug/ml )

Mean APACHE II scores same at

baseline (25)

Acidosis more common under original

protocol than amended (46% vs. 26%)

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Effect of Protocol Change:

DNR Orders

79 (16)50 (10)Amendment A

64 (18)57 (16)Original

Placebo

N (%)

rhAPC

N (%)

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Mortality:Original vs. Amended Protocol

Strata Total Therapy Died by

Day 28

Original 360 rhAPC 102 (28)360 Placebo 109 (30)

720 P=0.5665

Amended 490 rhAPC 108 (22)480 Placebo 150 (31)

970 P=0.0012

1690

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Cumulative 28 Day

Mortality Over Time

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Sensitivity Analysis:

Patients on Pre-Amendment Not

Eligible Under Post-Amendment

Meet

New

Incl

rhAPCMortality

Total N N (%)

PlaceboMortality

Total N N (%)

RR 95%

CI

No 41 14 (34) 40 17 (43) 0.80 0.46,

1.40

Yes 319 88 (28) 320 92 (29) 0.96 0.75,1.23

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Summary of Efficacy

28 day all cause mortality

24.7% rhAPC vs. 30.8% placebo

(p=0.005)

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Summary of Efficacy

Additional analyses suggest

treatment benefit predominant:

3rdand 4thAPACHE II quartile

laboratory evidence DIC

not on heparin

> 50 years of age

2 OF

shock

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Outline of Presentation

Pediatrics

Adult safety phase 2


Immunogenicity

Summary

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Pediatric Database

No controlled efficacy trials

Total Pediatric data base - 121 pts

Safety PK/PD sepsis study - 83 pts.

Purpura Fulminans - 14 pts.

Additional uncontrolledtrials - 24 pts.

Pediatric Sepsis Study vs Adult Phase 3

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Pediatric Sepsis Study vs. Adult Phase 3Type of Organ Failure (% of Patients)

0%

20%

40%

60%

80%

100%

Cardiovascular Respiratory Hematologic Renal

Pediatric (N=32) Adult (N=1690)


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Pediatric Sepsis Study vs. Adult Phase 3

# of Organ Failures (% of Patients)

0%

10%

20%

30%

40%

50%

60%

One Two Three Four



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Primary Site of Infection (% of Patients)

0%

10%

20%

30%

40%

50%

60%

Blood CNS Lung Intra-Abd UTI



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Type of Pathogen (% of Patients)

0%

5%

10%

15%

20%

25%

30%

35%

Gram Positive Gram Negative Mixed Gram



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Predicted Mortality (% of Patients)

0%

5%

10%

15%

20%

25%

Pediatric Index of

Mortality

APACHE II Score



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Actual Mortality (% of Patients)

0%

5%

10%

15%

20%

14 Day Mortality 14 Day Mortality



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Safety Parameters (% of Patients)

0%

20%

40%

60%

80%

100%

Serious

Bleeding

Events

Bleeding

AE

SAE AE


P di t i S f t

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Pediatric Safety

1 death due to intracranial hemorrhage 3 Bleeding SAE

6y/o nasopharyngeal hemorrhage

5 month/old with petechial cerebralhemorrhage

15 y/o with UGI hemorrhage

P di t i S

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Pediatric Summary

Limited uncontrolled database Similar

PK/PD data

Serious bleeding events Different

Organ failure - CV

Primarily one organ failure Site of infection - blood, lung, CNS

Type of pathogen - gram negative

10% 14 day mortality

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Pediatrics



Immunogenicity

Summary

Safety Phase 2

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Safety Phase 2

Patient Population

Exclusion of patients with:

high risk of bleeding

on medications affecting coagulation

Specific criteria to start and stop the

infusion

related to procedures related to coagulation parameters

Safety Phase 2

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Safety Phase 2

Patient Deaths by TreatmentGroup

Treatment group 48 hrinfusion

96 hrinfusion

12 ug/kg/hr 3/11 (27%) 5/14 (36%)

18 ug/kg/hr 3/11 (27%) 7/15 (47%)

24 ug/kg/hr 0/12 (0%) 5/15 (33%)

30 ug/kg/hr 3/12 (25%) Not Studied

All Placebo 14/41 (34%)

S f t Ph 2

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Safety Phase 2

SAE during infusion period by treatmentgroup

48 hr rhAPC 7/46 (15%)

96 hr rhAPC 12/44 (27%) All Placebo 10/41 (24%)

Bleeding events reported as significant

3/90 (3%) No intracranial hemorrhages

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Pediatrics



Immunogenicity

Summary

Safety Phase 3

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Safety Phase 3Deaths Attributable to Hemorrhage During

the Infusion Period 850 patients in the rhAPC treatment arm

2 intracranial hemorrhage (ICH)

1 pulmonary hemorrhage 1 thoracic hemorrhage

840 patients in the placebo arm No Deaths attributable to hemorrhage

Ongoing Open-Label Trials

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Ongoing Open Label Trials

New Intracranial Hemorrhages

During the Infusion Period 13 new ICH in 520 patients enrolled in

ongoing safety studies

8 of these occurred during the infusion

period

Infusion period event rate

8/520 1.5% 95% CI (.67, 3.01)

Serious Bleeding Events

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Protocol Definition

Intracranial hemorrhage

Life-threatening bleed

Transfusion of > 2 units (phase 2) or > 3

units (phase 3) PRBC on 2 consecutive

days

Met other criteria for a SAE


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Infusion Period

Site rhAPC (n=850) Placebo (n=840)

Total 20 8

Gastrointestinal 5 4

Intra-abdominal 2 3Intra-thoracic 4 0

Retroperitoneal 3 0

Intracranial hemorrhage 2 0

Undefined hemorrhage 1 1Genitourinary 2 0

Skin/soft tissue 1 0

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Safety During the Infusion Period

2% 1%

19%

11% 7% 7%

69% 65%

0%10%

20%

30%

40%50%

60%

70%

Serious

Bleeding

Event

Bleeding

AE

SAE AE

rhAPC (N=850) Placebo (N=840)

First APACHE II Quartile

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First APACHE II QuartileEvents During Drug Infusion

Event (%)

rhAPC Placebo Treatment

differenceBleedingAE

38/218 (17%) 17/210 (8%) 9%

Serious

BleedingEvent

9/218 (4%) 0 4%

Subjects Requiring Transfusion

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Subjects Requiring Transfusion

During 28 Day Study Period

rhAPCN (%)

PlaceboN (%)

PRBC 533/850 (63) 490/840 (58)

FFP 200/850 (24) 162/840 (19)

Platelets 114/850 (13) 96/840 (11)

Serious Bleeding Events in

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Patients Laboratory Evidence of

DIC

rhAPC

N (%)

Placebo

N (%)Subjects in DIC 28/800 (4) 16/774 (2)

Subjects withunknown DIC 2/49 (4) 1/66 (2)

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Bleeding Events and Baseline

Coagulation Factors

Pooled phase 2 and phase 3 data

rhAPC = 940 Placebo = 881

Baseline APTT and Adverse

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Baseline APTT and Adverse

Bleeding Events

ActivatedPartial

ThromboplastinTime

rhAPCN (%)

PlaceboN (%)

APTT< 2x ULN 147/825 (18) 80/761 (11)

APTT> 2x ULN 9/44 (20) 5/37 (14)

Baseline PT and Adverse

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Baseline PT and Adverse

Bleeding Events

ProthrombinTime

rhAPCN (%)

PlaceboN (%)

PT < 1.2x ULN 49/354 (14) 29/311 (9)

PT > 1.2x ULN 108/516 (21) 55/484 (11)

Baseline Platelet Count and

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Baseline Platelet Count and

Adverse Bleeding Events

Platelet Count rhAPC

N (%)

Placebo

N (%)Platelet > 50,000/mm

3133/771 (17) 71/709 (10)

Platelet < 50,000/mm3 5/19 (26) 7/24 (29)


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Subjects who Received Heparin(Received DVT prophylactic dose at baseline up to day 5)

Treatment rhAPCEvents (%)

PlaceboEvents (%)

Received

Heparin

15/634 (2) 5/637 (1)

No Heparin 5/216 (2) 3/203 (1)

Bleeding Adverse Events in

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Bleeding Adverse Events in

Subjects who Received Heparin(Received DVT prophylactic dose at baseline up to day 5)

Treatment rhAPCEvents (%)

PlaceboEvents (%)

Received

Heparin

111/634 (18) 67/637 (11)

No Heparin 49/216 (23) 24/203 (12)

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Subgroups

No differences in safety profile were

observed in the following sub-groups

Gender

Origin

Age

Baseline Surgical Status

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Baseline Surgical StatusPhase 2 and 3 Data

Mortality

Emergency post-op patient with sepsis rhAPC 56/186 (30%) placebo 49/187 (26%)

Elective post-op patient with sepsis rhAPC 20/63 (32%) placebo 22/59 (37%)

Bleeding Rate

Similar bleeding adverse event ratebetween post-op and non operative

patients

rhAPC Steady State Concentration

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yand Adverse Events

(N=326, median 45 ng/ml)

0%

5%10%

15%

20%

25%

30%

Mortality >=1 SAE >=1 SAE

infusion

BE-SAE BE-SAE

infusion

Median and Below 14-45 ng/mlAbove Median 45.1-390 ng/ml

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Pediatrics



Immunogenicity

Summary

Immunogenicity

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Immunogenicity

3 tier testing1 Chemiluminescent Binding Assay (CBA)

2 Inhibition Chemiluminescent Binding Assay

3 Neutralizing antibody assay (APTT)

Assay Evaluation

Outstanding issues regarding sensitivity,

specificity and quantificationDifficult to assess true incidence of Anti-APC

antibodies

Immunogenicity

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Immunogenicity

Patients tested: Phase 2 and 3 942 subjects - 370 tested

5 positive patients by tier 1 test

(Binding assay)

2 positive patients by tier 2 tests(Inhibition assay)

0 positive patient by tier 3 tests(Neutralizing)

Patients Positive for Specific

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Patients Positive for Specific

anti-APC Ab(Inhibition Assay)

Phase 2 Patient no clinical sequalae

Phase 3 Patient Superficial and deep venous thrombosis

alive at day 28 study end

follow-up revealed subject died at day 36 of multi-organ failure

8/13/2019 3797s1_02_Forsyth

82/87


Pediatrics



Immunogenicity

Summary

Pediatric Summary

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83/87

Pediatric Summary

No controlled studies to support efficacy

Limited patient population

Compared to adults similar drug effects

different disease characteristics

low mortality rate/similar adverse event rate

Summary of Safety - Adults

8/13/2019 3797s1_02_Forsyth

84/87

Summary of Safety Adults

Subjects enrolled in the phase 2 and 3trials were carefully selected to minimize

bleeding risk

Increased rate during infusion in rhAPCtreated subjects compared to placebo of:

bleeding adverse events

19% vs.11% respectively serious bleeding events

2% vs. 1% respectively

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85/87


Phase 3 trial

4 deaths attributed to bleeding during infusion

of rhAPC (2 ICH) - none in placebo rate of ICH during infusion of rhAPC - 0.2%

Subsequent open label trials (N=520)

13 new intracranial hemorrhages 8 during the infusion period

Rate of ICH during infusion (8/520) - 1.5%

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86/87


One subject with anti-APC Ab

developed DVT

No other pattern of adverse eventsnoted comparing rhAPC to placebo

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87/87

Safety Conclusion

Difficult disease process to detect

adverse events

Trend in intracranial hemorrhage True risk uncertain

Date post:	04-Jun-2018
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3797s1_02_Forsyth

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